The present application is related to Merck 18996, U.S. Ser. No. 08/059,038, filed May 7, 1993, 18996IA, U.S. Ser. No. 08/235,576, filed Apr. 29, 1994, Merck 19251, Merck 19114 and Merck 19115.
The present invention is concerned with a process for synthesizing intermediates for compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as Compound J in the Examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
The invention described herein concerns the conversion of indene to chiral indan oxide, as illustrated by the following scheme. ##STR1##
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313,277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. The end product compounds, including certain oligopeptide analogs that can be made from the novel intermediates and processes of this invention, are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, Compound J therein, also illustrated in the Examples below.
The present application discloses an improved process to make, in substantial enantiomeric purity, 1(S)-hydroxy-2(R)-hydroxy indan of the structure ##STR2## which is a sidechain group of Compound J, which is a potent inhibitor of HIV protease.
Previous attempts at synthesis involve inefficient production of the racemate 1(.+-.)-amino-2(.+-.) hydroxy indan from the racemic indene oxide. Applicants have discovered a fungal preparation that bioconverts indene to predominantly trans-(2S,1S)-bromo-indanol. Further, applicants have found that the adjustment of the pH of the reaction mixture to about 12 quantitatively converts trans-(2S,1S)-bromo-indanol to (1S,2R) indan oxide (85% ee). Prior methods of preparing the same chiral oxide from indene typically gave yields of about 10% or less. Conversion of (1S,2R)-indan oxide to (1S,2R)-indandiol (82% ee) is readily performed.